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Multitarget‐Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases
Abstract
The therapy of complex neurodegenerative diseases requires the development of multitarget‐directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H 3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small‐molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood–brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg−1 i.p.) also significantly improved lipopolysaccharide‐induced cognitive deficits.
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“In vivo efficacy studies showed that administration of 36 at 1 mg/kg is able to restore the cognitive deficit in lipopolysaccharide (LPS)-treated mice.120”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [120]
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Metadata
- Authors
- Bautista‐Aguilera, Ó. M., Hagenow, S., Palomino‐Antolin, A., Farré‐Alins, V., Ismaili, L., Joffrin, P., Jimeno, M. L., Soukup, O., Janočková, J., Kalinowsky, L., Proschak, E., Iriepa, I., Moraleda, I., Schwed, J. S., Romero Martínez, A., López‐Muñoz, F., Chioua, M., Egea, J., Ramsay, R. R., Marco‐Contelles, J., & Stark, H.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Heinrich Heine University Düsseldorf (DE)
- Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica Hospital Universitario de la Princesa Calle de Diego de León, 62 28006 Madrid Spain
- Hospital Universitario de La Princesa (ES)
- Neurosciences Intégratives et Cliniques EA 481 Université Bourgogne Franche-Comté Rue Ambroise Paré 25000 Besançon France
- University of St Andrews (GB)
- University Hospital Hradec Králové (CZ)
- Goethe University Frankfurt (DE)
- Universidad de Alcalá (ES)
- Departamento de Toxicología y Farmacología Facultad de Veterinaria, UCM Av. Puerta de Hierro, s/n 28040 Madrid Spain
- Universidad Camilo José Cela C/ Castillo de Alarcón, 49 28692 Villanueva de la Cañada Madrid Spain
- Laboratorio de Química Médica Instituto de Química Orgánica General CSIC and Centro de Química Orgánica “Lora-Tamayo”, CSIC C/ Juan de la Cierva 3 28006 Madrid Spain
- Corresponding author
- Egea, Javier
- Stark, Holger
- ORCID
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2017-09
- Volume
- 56
- Issue
- 41
- Pages
- 12765-12769
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2751976716
- Cited by
- 105
- References
- 29
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 9 · 2023: 8 · 2022: 13 · 2021: 15 · 2020: 13 · 2019: 17 · 2018: 16
- FWCI
- 9.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- St Andrews Research Repository (St Andrews Research Repository) (submittedVersion)
- Funders
- Ministerio de Economía y Competitividad (SAF2012-33304, SAF2015-65586-R)
- Universidad Camilo José Cela (2015-12, 2014-35 and 2015-21)
- Fondo de Investigaciones Sanitarias (CP14/00008, PI16/00735)
- MHCZ-DRO (UHHK 00179906)
- European Cooperation in Science and Technology (CM1103, CM15135)
- Deutsche Forschungsgemeinschaft (PRO 1405/2-2, PRO 1405/4-1, SFB 1039 A07, INST208/664-1)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Keywords
- cholinesterase inhibition, acetylcholinesterase, butyrylcholinesterase, monoamine oxidase inhibition, indole derivatives, neurodegenerative diseases, neuroprotection, antioxidant activity, blood-brain barrier penetration, cognitive impairment
- MeSH terms
- Animals, Antioxidants, Blood-Brain Barrier, Cholinesterase Inhibitors, Humans, Indoles, Ligands, Monoamine Oxidase Inhibitors, Piperidines, Drug Design, Neuroprotective Agents, Neurodegenerative Diseases, Mice, Histamine H3 Antagonists, Cognitive Dysfunction
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